Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes.
Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-06-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010445&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849316762913341440 |
|---|---|
| author | Eric Van Buren Giorgia Radicioni Sarah Lester Wanda K O'Neal Hong Dang Silva Kasela Suresh Garudadri Jeffrey L Curtis MeiLan K Han Jerry A Krishnan Emily S Wan Edwin K Silverman Annette Hastie Victor E Ortega Tuuli Lappalainen Martijn C Nawijn Maarten van den Berge Stephanie A Christenson Yun Li Michael H Cho Mehmet Kesimer Samir N P Kelada |
| author_facet | Eric Van Buren Giorgia Radicioni Sarah Lester Wanda K O'Neal Hong Dang Silva Kasela Suresh Garudadri Jeffrey L Curtis MeiLan K Han Jerry A Krishnan Emily S Wan Edwin K Silverman Annette Hastie Victor E Ortega Tuuli Lappalainen Martijn C Nawijn Maarten van den Berge Stephanie A Christenson Yun Li Michael H Cho Mehmet Kesimer Samir N P Kelada |
| author_sort | Eric Van Buren |
| collection | DOAJ |
| description | Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822-1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB. |
| format | Article |
| id | doaj-art-15ff002556a14a7bb60b42d94e480aed |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2023-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-15ff002556a14a7bb60b42d94e480aed2025-08-20T03:51:29ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-06-01196e101044510.1371/journal.pgen.1010445Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes.Eric Van BurenGiorgia RadicioniSarah LesterWanda K O'NealHong DangSilva KaselaSuresh GarudadriJeffrey L CurtisMeiLan K HanJerry A KrishnanEmily S WanEdwin K SilvermanAnnette HastieVictor E OrtegaTuuli LappalainenMartijn C NawijnMaarten van den BergeStephanie A ChristensonYun LiMichael H ChoMehmet KesimerSamir N P KeladaHyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822-1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010445&type=printable |
| spellingShingle | Eric Van Buren Giorgia Radicioni Sarah Lester Wanda K O'Neal Hong Dang Silva Kasela Suresh Garudadri Jeffrey L Curtis MeiLan K Han Jerry A Krishnan Emily S Wan Edwin K Silverman Annette Hastie Victor E Ortega Tuuli Lappalainen Martijn C Nawijn Maarten van den Berge Stephanie A Christenson Yun Li Michael H Cho Mehmet Kesimer Samir N P Kelada Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes. PLoS Genetics |
| title | Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes. |
| title_full | Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes. |
| title_fullStr | Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes. |
| title_full_unstemmed | Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes. |
| title_short | Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes. |
| title_sort | genetic regulators of sputum mucin concentration and their associations with copd phenotypes |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010445&type=printable |
| work_keys_str_mv | AT ericvanburen geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT giorgiaradicioni geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT sarahlester geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT wandakoneal geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT hongdang geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT silvakasela geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT sureshgarudadri geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT jeffreylcurtis geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT meilankhan geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT jerryakrishnan geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT emilyswan geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT edwinksilverman geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT annettehastie geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT victoreortega geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT tuulilappalainen geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT martijncnawijn geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT maartenvandenberge geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT stephanieachristenson geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT yunli geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT michaelhcho geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT mehmetkesimer geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes AT samirnpkelada geneticregulatorsofsputummucinconcentrationandtheirassociationswithcopdphenotypes |